Project Summary/Abstract Schizophrenia is a devastating and debilitating disorder that affects about 1% of the population and is characterized by a range of symptoms including delusions, hallucinations, impaired cognitive function, mood disturbances and social withdrawal. Little is known about the neuropathology of schizophrenia, yet imaging studies of its earliest stages have the potential to identify initial pathologic traces preceding psychosis onset. New research approaches now allow clinicians to investigate prodromal schizophrenia subjects (prodromes) who experience attenuated psychotic symptoms, and are at high-risk for developing schizophrenia. Diffusion MRI is a promising imaging technique for prodromes, since it consistently and reliably identifies abnormalities in all stages of schizophrenia. However, current diffusion MRI biomarkers and analysis methods have limited sensitivity and poor specificity to the underlying microstructural pathology, which pose barriers to further understanding the etiology of schizophrenia, and to new developments in pharmacological treatment. The goal of this proposal is to develop tools and apply next generation diffusion MRI biomarkers, such as free- water imaging, neurite density, neurite orientation dispersion, and Kurtosis. These biomarkers improve specificity and sensitivity of currently available measures, and are more suited to identify subtle pathologies. Our previous research suggests that neurodevelopmental, neuroinflammatory and neurodegenerative microstructural pathologies are involved in schizophrenia. We hypothesize that neuroinflammation is the dominant pathology responsible for triggering attenuated psychotic symptoms, and that abnormal neurodevelopment, which changes how the brain appears or grows, may be a predisposition for psychosis. Using next generation diffusion MRI biomarkers can distinguish between these micropathologies, which will help explaining their association with attenuated psychotic symptoms, and reveal their role in psychosis onset. Large-scale studies, such as the North American Prodrome Longitudinal Study (NAPLS), have already collected large datasets of CHR that include dMRI data, and this data will be available to us. Our approach is to leverage from these existing data and utilize it to study the pathological correlates of prodromal symptoms, unlike previous studies that focused on risk for conversion to SZ. The assembled unprecedentedly large data (n>700) provide ample sensitivity to identify subtle prodromal pathologies. A highly trained team of computer scientists and clinical neuroscience researchers will work to develop novel tools for next generation diffusion MRI biomarkers in order to localize and to characterize the neurobiology that underlies prodromal symptomatology. The results of this study will have an important impact on our understanding of biological mechanisms underlying the initial stages of schizophrenia, and will lead to improved diagnosis and possibly new treatments that target such phenomena as neuroinflammation.